Multiple sclerosis (MS) remains the leading cause of neurological nontraumatic disability for young adults in North America and outcomes of current therapy are often unsatisfactory. This P50 competing renewal application directly extends and amplifies our research during the previous two cycles of support. We focus here on gray matter pathology, extending our previous work addressing interlinked hypotheses regarding the destructive inflammatory and neurodegenerative processes in MS patients. The P50 encompasses several unique resources including a rapid-autopsy program which has yielded insights into MRI-pathology correlations; a longitudinal MRI cohort which has illuminated the mechanisms underlying brain atrophy in MS; and newly-recruited, a series of MS biopsy cases which can be studied to understand cortical pathology early in MS. Core A: Tissue acquisition, imaging, biostatistics. administration (R Ransohoff) will establish, maintain and distribute a unique resource of MS autopsy tissue with dedicated postmortem imaging, as well as coordinate database management and provide administrative and biostatistical support for all projects. Project 1: Cortical demyelination and leukocyte trafficking early in MS (R Ransohoff; C Lucchinetti) will address the hypothesis that meningeal inflammation and cortical demyelination early in the MS process are implicated in facilitating white matter demyelination. This project will also address mechanisms of selective leukocyte trafficking to meninges and cortex. Project 2: Cellular and molecular mechanisms of cortical remyelination in MS patients (B Trapp) will examine cortical demyelination and remyelination in MS brains, and characterize both the cells mediating repair and the factors that inhibit repair. Project 3: Gray matter atrophy in multiple sclerosis (E Fisher) will use novel quantification techniques, developed as part of the P50 research, address in a longitudinal MRI cohort, the relationship between gray matter atrophy and white matter lesions as well as normal-appearing white matter changes. This project will also define relationships between gray matter atrophy and neuropsychological changes. Project 4: Gray matter atrophy in multiple sclerosis: Clinical implications (R Rudick) will extend the use of our new MRI analytic software to define the time course of gray matter atrophy, and evaluate the effects of immunomodulatory therapy, using files from completed clinical trials of a diversity of agents Extending our established research approaches to address gray matter pathology in MS will provide new insights into disease mechanisms and identify novel therapeutic targets.